Proper function of individual cells and entire organisms depends upon information transfer from the extracellular environment to the cytoplasm. Most signals must be transduced via proteins that span cellular membranes. Many receptor proteins do not act as simple, binary “toggle switches,” with only signaling-active and signaling-inactive states. Rather, they behave in vivo as nuanced interpreters of molecular information. This behavior enables the transmission of diverse messages based on variations in agonist structure. “Biased agonism” is one widely-studied manifestation of this complexity that has been documented for multiple G protein-coupled receptors (GPCRs).1,2 Signal transduction via these GPCRs involves multiple intracellular partners, only some of which are G proteins. A natural agonist activates these alternative signaling pathways in a given proportion, for a given cell type and environment. Other agonists are designated as biased relative to this benchmark if they lead to a different balance of signal intensities among the available pathways.3 These differences in signal transduction pattern can arise from subtle agonist-dependent variations in receptor conformation.4 
The biased agonism paradigm is not the only mechanism by which diversity in GPCR signaling can arise from variations in agonist-bound receptor conformation. The parathyroid hormone receptor-1 (PTHR-1), for example, has two distinct functional states. These are depicted schematically in FIG. 1. The RG functional state, shown to the right in FIG. 1, forms when the intracellular portion contacts a given G protein (designated GαND in FIG. 1). In contrast, the R0 functional state, shown to the left in FIG. 1, forms independent of G protein association.5,6 An agonist's affinity for the RG state is predicted to correlate with PTHR-1 activation potency, while an agonist's R0 affinity correlates with the duration of some in vivo responses.7,8 Natural agonists for PTHR-1 include parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), which display similar affinity for the RG state but differ in their affinity for the R0 state.7 This behavior cannot be described as biased agonism because PTH and PTHrP seem to activate the same intracellular signaling mechanisms,9 but there is a clear mechanistic parallel to the bias paradigm in that agonists with different receptor-state selectivities cause different biological effects.7,8,10 
Receptor state-selective agonists are highly prized because these molecules can serve as powerful tools for elucidating signal-transduction mechanisms, and they may give rise to therapeutic agents with minimal deleterious side effects.1,2 At present, there is no way to design such agonists via rational methods.
In terms of mammalian disease states, including humans, the umbrella term hypoparathyroidism is used to designate any decreased function of the parathyroid glands with concomitant underproduction of PTH. This then leads to low levels of calcium in the blood. The main symptoms of hypoparathyroidism are the result of the low blood calcium level, which interferes with normal muscle contraction and nerve conduction. As a result, people with hypoparathyroidism experience a number of unsettling symptoms, including paresthesia (an unpleasant tingling sensation around the mouth and in the hands and feet), muscle cramps, and tetany (severe spasms that affect the hands and feet). Many subjects suffering from hypoparathyroidism also report somewhat vague but pervasive symptoms such as fatigue, headaches, bone pain and insomnia. Chronic hypoparathyroidism is conventionally treated with vitamin D analogs and calcium supplementation. However, such treatments are contra-indicated in many patients due to potential renal damage. The N-terminal fragment of parathyroid hormone, PTH (1-34), has full biological activity. Teriparatide (marketed in the U.S. by Eli Lilly & Co. under the trademark “Forteo”) is a recombinant form of PTH approved for use in the treatment of osteoporosis.